The broad long-term goal of the candidate is to develop new strategies to improve cardiovascular risk assessment. The goal of this proposal is to evaluate the association of two measures of arterial function - endothelial function and arterial compliance - with conventional and novel risk factors on one hand and with sub-clinical atherosclerosis on the other hand. The hypothesis is that these measures of arterial function mediate the deleterious effects of conventional and novel risk factors and are associated with coronary atherosclerosis in asymptomatic individuals. The novel risk factors to be studied include the 'conditional' risk factors (homocysteine, fibrinogen, lipoprotein (a), triglycerides, small dense low density lipoprotein (LDL), and C-reactive protein and polymorphisms in selected candidate genes (endothelial nitric oxide synthase and angiotensin converting enzyme). Endothelial function will be assessed by brachial artery reactivity using vascular ultrasound and arterial compliance assessed by pulse wave velocity using applanation tonometry. Because the effects of novel risk factors on arterial function may depend on the background of conventional risk factors, the measures of arterial function will be obtained in two well-characterized, community-based cohorts with different burdens of conventional risk factors. In both cohorts, coronary artery calcification measured by electron beam computed tomography, a quantitative measure of subclinical atherosclerosis, is available at no cost for the present proposal. Candidate: To obtain additional skills necessary for a career as an independently funded clinical investigator, the candidate will complete courses in research design, biostatistics and genetic epidemiology. Based on the training and experience obtained, the candidate plans to submit an R01 application in year 4 of the award building on the studies proposed in this application. Environment: The candidate is supported by an accomplished team of mentors and consultants and has access to unparalleled resources at Mayo Clinic Rochester for patient-oriented research including one of the finest General Clinical Research Centers in the country.